This is a collaborative project with other NASA investigators who are characterizing mouse models of human lung and colon cancers. Data from both the investigator’s laboratory and the literature suggest that epigenetics play a significant role in carcinogenic processes. By describing the changes in DNA methylation and miR regulation of gene expression for these mice, investigators will provide NASA with mechanistic data regarding carcinogenic initiation and progression. By using normal, cancer, and metastatic cancer cell lines they will obtain information regarding epigenetic changes that occur during carcinogenesis based on stage. For example, loss of control of gene expression for extracellular matrix (ECM) remodeling genes may foster metastatic behavior in colon cancer. For this reason they aim to include ECM gene promoter DNA methylation and gene expression among the loci evaluated in this study to the hypothesis that dis-regulation of epigenetic marks and gene expression changes with disease progression. Similarly, the work of other NASA investigators suggests that they will see epigenetically regulated differences among cell lines in expression of inflammatory response pathway gene regulation among lung cell lines. These experiments will provide information regarding radiation responses of these mouse tissues and human cell lines based on the LET of the radiation used. Abnormal epigenetic silencing of genes can occur at a variety of times during tumor progression. If so, does radiation exposure push normal cells to a cancer phenotype and cancer cells to a metastatic phenotype? This question is of importance to NASA since astronauts are of an age where they likely go into missions with precursor lesions. It is important to understand whether their occupational radiation exposures lead to increased cancer risk.
This study had the following specific aims:
- Evaluate normal and cancer cell lines from lung and colon for responses to low dose high LET radiation exposure.
- Establish epigenetic profiles for in vivo radiation induced cancers in mouse models of human lung and colon cancers.
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Investigators planned to irradiate lung cell lines that are both normal and cancerous using 600 MeV/µ 56Fe ions. These cell lines will then be propagated for analysis of delayed changes in DNA methylation of gene promoters and repeat elements within the genome, and mRNA and miR expression.
The plan for this project was to evaluate epigenetic mechanisms in mouse tissues from other NASA investigators involved in the Lung and Colon cancer NSCORs. In this first year, they have begun liaising with other NASA investigators to establish which experimental groups (genotypes, time points, doses, radiations) will have the highest priority and provide the most useful information. They have also established what is required with regards to tissue collection and preservation. They have obtained the majority of the cell lines that will be used in this study and began propagating them and archiving the appropriate cells stocks. In conjunction with another of our NASA funded projects, they have developed the pyrosequencing assays that will be used in the analysis of DNA methylation. During this process they have confirmed a tissue-specific effect of irradiation on DNA methylation in the lung of normal male mice.
This study is continued on NNX13AK69G with the same title due to the investigator’s move to a new institution.